Synthesis and self-assembly of multiple thermoresponsive ...

Synthesis and Self-Assembly of MultipleThermoresponsive Amphiphilic Block Copolymers

A dissertation submitted to

Potsdam 2011

Presented by

University of Potsdam

for the degree of

doctor rerum naturalium

(Dr. rer. nat.)

in Macromolecular Chemistry

Jan Wei

Department of Chemistry

Supervisor Prof. A. Laschewsky

Published online at the Institutional Repository of the University of Potsdam: URL http://opus.kobv.de/ubp/volltexte/2011/5336/ URN urn:nbn:de:kobv:517-opus-53360 http://nbn-resolving.de/urn:nbn:de:kobv:517-opus-53360

Danksagung

Mein Dank geht an Prof. Dr. A. Laschewsky fr die Mglichkeit meine Dok-

torarbeit in seiner Gruppe anfertigen zu knnen und fr die Untersttzung

und Diskussionen whrend dieser Zeit. Ferner mchte ich Dr. J. van Heijst

und Dr. H. Regger, der das Ende dieser Arbeit aufgrund tragischer Um-

stnde leider nicht mehr miterleben kann, fr die Mglichkeit danken, tem-

peraturabhngige NMR Spektren an der ETH Zrich messen zu knnen,

Dr. C. Bttcher fr die TEM Messungen, Prof. Dr. S. Beuermann und Herrn

S. Prentzel fr SEC Messungen, Dr. N. Hildebrandt und Dr. S. Stufler fr

den Zugang zum Fluoreszenzspektrometer sowie Prof. Dr. J. Beckmann und

Prof. Dr. H. Frauenrath fr hilfreiche Diskussionen.

Ausserdem mchte ich Dr. Achille Bivigou-Koumba fr die zahlreichen

Diskussionen und die praktischen Ratschlge, besonders in der An-

fangsphase meiner Promotionszeit und Maike Lukowiak fr den Zugang zu

einiger Literatur danken.

Des Weiteren mchte ich Dr. Nezha Badi fr die hilfreichen Diskussionen,

Korrekturen dieser Arbeit, die Untersttzung sowie fr die wundervolle Zeit

auch neben der Arbeit, die meine drei Jahre in Potsdam unvergesslich macht,

von ganzem Herzen danken.

Zu guter Letzt geht noch ein besonderer Dank an meine Familie, insbeson-

dere an meine Mutter fr ihre fortwhrende Untersttzung in jeglicher Hin-

sicht.

List of Publications

Parts of this Ph. D. thesis were published in scientific journals and were presented in oral

presentations as well as on posters at several occasions by the author of this thesis.

Publications (peer-reviewed)

[1] Universal Polymer Analysis by 1H NMR Using Complementary Trimethylsilyl End

Groups, M. Pch, D. Zehm, M. Lange, I. Dambowsky, J. Weiss, A. Laschewsky, J. Am.

Chem. Soc., 2010, 132, 8757-8765.

[2] Self-Assembly of Double Thermoresponsive Block Copolymers End-capped with

Complementary Trimethylsilyl Groups, J. Weiss, C. Bttcher, A. Laschewsky, Soft Mat-

ter, 2011, 7, 483-492.

[3] Temperature Induced Self-Assembly of Triple Thermoresponsive Triblock Copoly-

mers in Aqueous Solution, J. Weiss, A. Laschewsky, Langmuir, 2011, 27, 4465-4473.

[4] Ferrocenyl (Meth)Acrylates in RAFT Polymerization, C. Herfurth, D. Voll, J. Buller,

J. Weiss, C. Barner-Kowollik, A. Laschewsky, submitted to J. Polym. Sci. Part A: Polym.

Chem.

Publications (to be submitted)

[5] Water-soluble Random and Alternating Copolymers of Styrene Monomers with

Adjustable Lower Critical Solution Temperature, J. Weiss, A. Li, E. Wischerhoff,

A. Laschewsky*, to be submitted.

[6] Facile One-Step Synthesis of Double Thermosensitive Diblock Copolymers, J. Weiss,

A. Laschewsky*, to be submitted.

IV

Oral Presentations

[1] A Trimethylsilyl-labeled RAFT-Agent as NMR Probe for Reversible Block Copolymer

Self-Assembly, 13.07.2010, 43rd IUPAC World Polymer Congress, Glasgow, UK.

[2] Multistep Self-Assembly of Thermoresponsive Block Copolymer Surfactants,

03.05.2011, 45th International Detergency Conference (IDC), Dsseldorf, Germany.

Poster Contributions

[1] Temperature Induced Self-Assembly of Triple-Responsive Triblock Copolymers in

Aqueous Solutions, PhD Students Workshop Functional Soft Matter, Potsdam, Ger-

many, 2010.

[2] Temperature Induced Self-Assembly of Triple-Responsive Triblock Copolymers in Di-

lute Aqueous Solution, 43rd IUPAC World Polymer Congress, Glasgow, UK, 2010.

[3] Self-Assembly of Triple-Thermoresponsive Triblock Copolymers in Dilute Aqueous

Solution, Polymers in Biomedicine and Electronics - Biannual Meeting of the GDCh-

Division Macromolecular Chemistry and Polydays 2010, Berlin, Germany, 2010.

[4] Improving the IQ of Intelligent Block Copolymer Surfactants: Designs for Multiple

Switching, 6th European Detergency Conference, Fulda, Germany, 2010.

[5] Sequential Self-Assembly of Multiple Thermoresponsive Block Copolymers, Makro-

molekulares Kolloquium, Freiburg, Germany, 2011.

V

Summary

In the present thesis, the self-assembly of multi thermoresponsive block copolymers in di-

lute aqueous solution was investigated by a combination of turbidimetry, dynamic light

scattering, TEM measurements, NMR as well as fluorescence spectroscopy. The succes-

sive conversion of such block copolymers from a hydrophilic into a hydrophobic state in-

cludes intermediate amphiphilic states with a variable hydrophilic-to-lipophilic balance.

As a result, the self-organization is not following an all-or-none principle but a multistep

aggregation in dilute solution was observed. The synthesis of double thermoresponsive di-

block copolymers as well as triple thermoresponsive triblock copolymers was realized us-

ing twofold-TMS labeled RAFT agents which provide direct information about the average

molar mass as well as residual end group functionality from a routine 1H NMR spectrum.

First a set of double thermosensitive diblock copolymers poly(N-n-propylacrylamide)-b-

poly(N-ethylacrylamide) was synthesized which differed only in the relative size of the two

blocks. Depending on the relative block lengths, different aggregation pathways were found.

Furthermore, the complementary TMS-labeled end groups served as NMR-probes for the

self-assembly of these diblock copolymers in dilute solution. Reversible, temperature sensi-

tive peak splitting of the TMS-signals in NMR spectroscopy was indicative for the formation

of mixed star-/flower-like micelles in some cases.

T1 T2n m

Moreover, triple thermoresponsive triblock copolymers from poly(N-n-

propylacrylamide) (A), poly(methoxydiethylene glycol acrylate) (B) and poly(N-

ethylacrylamide) (C) were obtained from sequential RAFT polymerization in all possible

block sequences (ABC, BAC, ACB). Their self-organization behavior in dilute aqueous

solution was found to be rather complex and dependent on the positioning of the different

blocks within the terpolymers. Especially the localization of the low-LCST block (A) had a

large influence on the aggregation behavior. Above the first cloud point, aggregates were

VI

only observed when the A block was located at one terminus. Once placed in the middle,

unimolecular micelles were observed which showed aggregation only above the second

phase transition temperature of the B block. Carrier abilities of such triple thermosensitive

triblock copolymers tested in fluorescence spectroscopy, using the solvatochromic dye Nile

Red, suggested that the hydrophobic probe is less efficiently incorporated by the polymer

with the BAC sequence as compared to ABC or ACB polymers above the first phase transition

temperature.

In addition, due to the problem of increasing loss of end group functionality during the

subsequent polymerization steps, a novel concept for the one-step synthesis of multi

thermoresponsive block copolymers was developed. This allowed to synthesize double

thermoresponsive di- and triblock copolymers in a single polymerization step. The copoly-

merization of different N-substituted maleimides with a thermosensitive styrene derivative

(4-vinylbenzyl methoxytetrakis(oxyethylene) ether) led to alternating copolymers with vari-

able LCST. Consequently, an excess of this styrene-based monomer allowed the synthesis of

double thermoresponsive tapered block copolymers in a single polymerization step.

N OO

R

t0

RAFT or ATRP

OO

4

alternating block homopolymer

Furthermore, by using bifunctional initiators, even double thermosensitive binary tri-

block copolymers could be synthesized. Both types of polymers showed an aggregation be-

havior similar to the one of block copolymers obtained by the classical step-wise approach

indicating the successful one-step synthesis of multi responsive block copolymers.

VII

Zusammenfassung

Im Rahmen der vorliegenden Arbeit wurde die Selbstorganisation von mehrfach ther-

misch schaltbaren Blockcopolymeren in verdnnter wssriger Lsung mittels Trbungspho-

tometer, dynamischer Lichtstreuung, TEM Messungen, NMR sowie Fluoreszenzspek-

troskopie untersucht. Die schrittweise berfhrung eines hydrophilen in ein hydrophobes

Blockcopolymer beinhaltet ein oder mehr amphiphile Zwischenstufen mit einstellbarem

hydrophilen zu lipophilen Anteil (HLB). Dies fhrt dazu, dass die Selbstorganisation

solcher Polymere in Lsung nicht nur einem Alles-oder-nichts-Prinzip folgt sondern ein

mehrstufiges Aggregationsverhalten beobachtet wird. Die Synthese von doppelt thermisch

schaltbaren Diblockcopolymeren und dreifach thermisch schaltbaren Triblockcopolymeren

wurde durch sequenzielle RAFT Polymerisation realisiert. Dazu wurden zweifach TMS-

markierte RAFT Agentien verwendet, welche die Bestimmung der molaren Masse sowie der

verbliebenen Endgruppenfunktionalitt direkt aus einem 1H NMR Spektrum erlauben. Mit

diesen RAFT Agentien wurde zunchst eine Serie von doppelt thermisch schaltbaren Di-

blockcopolymeren aus Poly(N-n-propylacrylamid)-b-Poly(N-ethylacrylamid), welche sich

lediglich durch die relativen Blocklngen unterscheiden, hergestellt. In Abhngigkeit von der

relativen Blocklnge wurde ein unterschiedliches Aggregationsverhalten der Diblockcopoly-

mere in verdnnter wssriger Lsung beobachtet. Des Weiteren wirken die komplemen-

tr TMS-markierten Endgruppen als NMR-Sonden whrend der schrittweisen Aggregation

dieser Polymere. Reversible, temperaturabhngige Peakaufspaltung der TMS-Signale in der

NMR Spektroskopie spricht fr eine Aggregation in gemischte stern-/blumenartige Mizellen,

in denen ein Teil der hydrophoben Endgruppen in den hyrophoben Kern zurckfaltet.

T1 T2n m

Obendrein wurden dreifach thermisch schalbare Triblockcopolymere aus Poly(N-n-

propylacrylamid) (A), Poly(methoxydiethylen glycol acrylat) (B) und Poly(N-ethylacrylamid)

(C) in allen mglichen Blocksequenzen (ABC, BAC, ACB) durch schrittweisen Aufbau mit-

tels RAFT Polymerisation erhalten. Das Aggregationsverhalten dieser Polymere in verdnn-

VIII

ter wssriger Lsung war relativ komplex und hing stark von der Position der einzelnen

Blcke in den Triblockcopolymeren ab. Besonders die Position des Blocks mit der niedrig-

sten LCST (A) war ausschlaggebend fr die resultierenden Aggregate. So wurde oberhalb der

ersten Phasenbergangstemperatur nur Aggregation der Triblockcopolymere beobachtet,

wenn der A Block an einem der beiden Enden der Polymere lokalisiert war. Wurde der A

Block hingegen in der Mitte der Polymere positioniert, entstanden unimere Mizellen zwis-

chen der ersten und zweiten Phasenbergangstemperatur, welche erst aggregierten, nach-

dem der zweite Block (B) seinen Phasenbergang durchlief. Die Transportereigenschaften

dieser Triblockcopolymere wurden mittels Fluoreszenzspektroskopie getestet. Dazu wurde

die Einlagerung eines hydrophoben, solvatochromen Fluoreszenzfarbstoffes, Nilrot, in Ab-

hngigkeit der Temperatur untersucht. Im Gegensatz zu den Polymeren mit der Blockse-

quenz ABC oder ACB, zeigten die Polymere mit der Sequenz BAC eine verminderte Aufnah-

mefhigkeit des hydrophoben Farbstoffes oberhalb des ersten Phasenbergangs, was auf die

fehlende Aggregation und die damit verbundenen relativ kleinen hydrophoben Domnen

der unimolekularen Mizellen zwischen der ersten und zweiten Phasenbergangstemperatur

zurckzufhren ist.

Aufgrund des zunehmenden Verlustes von funktionellen Endgruppen whrend der RAFT

Synthese von Triblockcopolymeren wurde ein neuartiges Konzept zur Einschrittsynthese

von mehrfach schaltbaren Blockcopolymeren entwickelt. Dieses erlaubt die Synthese von

mehrfach schaltbaren Diblock- und Triblockcopoylmeren in einem einzelnen Reaktions-

schritt. Die Copolymeriation von verschiedenen N-substituierten Maleimiden mit einem

thermisch schaltbaren Styrolderivat (4-Vinylbenzylmethoxytetrakis(oxyethylene) ether) er-

gab alternierende Copolymere mit variabler LCST. Die Verwendung eines berschusses

dieses styrolbasierten Monomers erlaubt ferner die Synthese von Gradientenblockcopoly-

meren in einem einzelnen Polymerisationsschritt.

N OO

R

t0

RAFT or ATRP

OO

4

alternating block homopolymer

IX

Bifunktionelle Initiatoren ergaben, dem gleichen Reaktionsprinzip folgend, doppelt

schaltbare binre Triblockcopolymere. Die so hergestellten Blockcopolymere zeigten ein

vergleichbares Aggregationsverhalten in verdnnter wssriger Lsung wie Blockcopolymere,

die durch klassiche sequenzielle kontrolliert radikalische Polymerisation erhalten werden.

X

List of Abbreviations

AGET activator generated by electron transfer

anal. analysis

ARGET activators regenerated by electron transfer

ATRP atom transfer radical polymerization

b broad signal (NMR)

calcd calculated

CP cloud point

CRP controlled radical polymerization

CTA chain transfer agent

d doublet (NMR)

chemical shift (NMR)

DCM dichloromethane

DBPO dibenzoyl peroxide

DIEA diisopropylethylamine

DIPA diisopropylamine

DMF N,N-dimethylformamide

DMSO dimethylsulfoxide

DP average degree of polymerization

EI electron impact ionization

eq. equivalents

ESI electrospray ionization

FRP free radical polymerization

GPC gel permeation chromatography1H NMR proton nuclear magnetic resonance13C NMR 13carbon nuclear magnetic resonance

HMDS hexamethyldisilazane

HRMS high resolution mass spectrometry

HV high vacuum

IR infra red

J J coupling constant (NMR)

LFRP living free radical polymerization

m multiplet (NMR)

XI

M molar

[M]+ molecular ion (MS)

MDEGA methoxydiethylene glycol acrylate

Mn number average molecular weight

NDM N-decylmaleimide

NEA N-ethylacrylamide

NMM N-methylmaleimide

NMP nitroxide mediated polymerization

NMR nuclear magnetic resonance

NPA N-propylacrylamide

NPM N-propylmaleimide

NPEGM N-PEG750-maleimide

NSM N-ethylthiomethyl maleimide

NSOM N-ethylsulfoxymethyl maleimide

NtBAlaM N,N-maleoyl-L-alanine tert.-butylester

NtBGlyM N,N-maleoyl-L-glycine tert.-butylester

NTESM N-(3-triethylsilyl)propargyl maleimide

NTMSM N-(3-trimethylsilyl)propyl maleimide

PDI polydispersity index

PEG poly(ethylene glycol)

PEO poly(ethylene oxide)

ppm parts per million (NMR)

PS polystyrene

RAFT reversible addition fragmentation chain transfer

Rf retention or retardation factor (thin layer chromatography)

s singlet (NMR)

t triplet (NMR)

TBAF tetrabutylammonium fluoride

TEA triethylamine

TEM transmission electron microscopy

TEMPO 2,2,6,6-tetramethylpiperidinyloxyl

TES triethylsilyl

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

XII

TMS trimethylsilyl

TMSR TMS group on the R group of a TMS-labeled RAFT agent

TMSZ TMS group on the Z group of a TMS-labeled RAFT agent

TEGDME triethyleneglycol dimethylether

UV ultraviolet

VBTOE 4-vinylbenzyl methoxytetrakis(oxyethylene) ether

XIII

Contents

1 Scope and Motivation 1

2 Introduction 3

2.1 Controlled Radical Polymerization Techniques . . . . . . . . . . . . . . . . . . . 3

2.1.1 Nitroxide Mediated Radical Polymerization . . . . . . . . . . . . . . . . . 4

2.1.2 Atom Transfer Radical Polymerization . . . . . . . . . . . . . . . . . . . . . 6

2.1.3 Reversible Addition-Fragmentation Chain Transfer Polymerization . . . 8

2.2 Block Copolymer Self-Assembly . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

2.2.1 Stimuli Responsive Block Copolymers . . . . . . . . . . . . . . . . . . . . . 19

2.3 Alternating Copolymerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

2.3.1 Alternating Copolymers of Maleic Anhydride and Styrene . . . . . . . . . 31

2.3.2 Copolymerization of N-substituted Maleimides with Styrene . . . . . . . 33

2.3.3 One-Step Synthesis of Diblock Copolymers . . . . . . . . . . . . . . . . . 34

2.4 Previous Investigations at Potsdam University . . . . . . . . . . . . . . . . . . . . 35

2.4.1 Twofold TMS-Labeled RAFT-Agents . . . . . . . . . . . . . . . . . . . . . . 35

2.4.2 Mono and Double Responsive Triblock Copolymers . . . . . . . . . . . . 38

2.5 Objectives of this Thesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

3 Results and Discussion 43

3.1 Synthesis of RAFT-Agents and Monomers . . . . . . . . . . . . . . . . . . . . . . . 43

3.1.1 Synthesis of RAFT-Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

3.1.2 Synthesis of Monomers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

3.2 TMS-Labeled RAFT-Agents and Styrenes . . . . . . . . . . . . . . . . . . . . . . . 45

3.3 Sequential RAFT-Synthesis of Multiple Thermoresponsive Block Copolymers . 47

3.3.1 Synthesis and Solution Properties of Homopolymers . . . . . . . . . . . . 48

3.3.2 Double Thermoresponsive Diblock Copolymers . . . . . . . . . . . . . . . 49

3.3.3 Triple Thermoresponsive Triblock Copolymers . . . . . . . . . . . . . . . 68

XV

3.4 One-Step Synthesis of Multi Responsive Block Copolymers . . . . . . . . . . . . 85

3.4.1 Synthesis of Monomers and ATRP Initiators . . . . . . . . . . . . . . . . . 85

3.4.2 Homopolymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

3.4.3 Alternating Copolymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92

3.4.4 Diblock Copolymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

3.4.5 ABA and BAB Triblock Copolymers . . . . . . . . . . . . . . . . . . . . . . 105

4 Conclusions 111

5 Experimental 115

5.1 Instrumentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115

5.2 General Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116

5.3 RAFT-Agents and ATRP Initiators . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118

5.4 Monomers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120

5.4.1 Acrylamides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120

5.4.2 Acrylates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121

5.4.3 Styrenics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122

5.4.4 Maleimides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122

6 References 129

7 Appendix 143

XVI

1 Scope and Motivation

Hierarchically structured nanomaterials, as often present in biological systems, are typi-

cally obtained using a combined bottom-up and top-down approach.1 The top-down

approach, although still dominating in todays industries, will face increasing technologi-

cal challenges and might reach its physical limitations in the near future. By contrast, the

bottom-up approach aims to build up ordered structures from (macro)molecular precur-

sors, attempting to benefit from their built-in information for higher structure formation.

The propensity to hierarchical structure formation, thus, is programmed on the molecu-

lar level and translated into building blocks with a defined shape on the supramolecular

level. Accordingly, the self-organization of appropriate macromolecular building blocks is a

promising bottom-up route toward well-defined nanomaterials.24

Within this context, amphiphilic block copolymers in aqueous media represent an inter-

esting class of self-organizing molecules since they are known to form a variety of aggre-

gates such as spherical micelles, worm-like (i.e. cylindrical) micelles, as well as vesicles

in dilute aqueous solution.510 Especially, stimuli responsive polymers, also often referred

to as smart, found increasing attention in the last decade due to their potential applica-

tion in industry ranging from biomedical to material science.6 The ability to control the

aggregation behavior of stimuli-sensitive polymers may help to address future challenges in

nanoscience and provides fundamental knowledge for the design of smart materials with

tunable properties. This thesis aims at understanding how multi responsive block copoly-

mers self-assemble in aqueous solution and tries to develop solutions for current limitations

in polymer synthesis and characterization as well as investigation of the formed aggregates

on a molecular level.

1

2 Introduction

2.1 Controlled Radical Polymerization Techniques

Free radical polymerization (FRP) is widely used in order to obtain high molecular weight

polymers due to (i) the compatibility with a variety of monomers, such as (meth)acrylates,

(meth)acrylamides, styrenics, dienes as well as other vinylic monomers; (ii) its tolerance

against many functionalities within monomers and solvent, e.g., OH, NR2, COOH, CONR2,

SO3; (iii) its high compatibility with various reaction conditions (e.g., bulk, solution, emul-

sion, mini-emulsion, and suspension); (iv) its relatively low costs compared to other tech-

nologies. Although widely used in industry and research laboratories, FRP has a significant

drawback. The variety of possible termination reactions result in limited control over mo-

lecular weight, molecular weight distribution as well as end groups and architecture of the

desired polymers.11 Moreover, block copolymers with defined block sequences and prede-

termined relative block lengths are practically not accessible by conventional free radical

polymerization. In order to overcome these limitations and enable the synthesis of well de-

fined block copolymers, several controlled radical polymerization (CRP) techniques were

invented within the past two decades, such as nitroxide mediated polymerization12 (NMP),

atom transfer radical polymerization13 (ATRP), or reversible addition-fragmentation chain

transfer polymerization14 (RAFT). Before the discovery of the CRP principle, living ionic

polymerizations were one of the few available tools to achieve control over molecular weight

and architecture with low polydispersities. The major disadvantages of ionic polymeriza-

tions, however, are the very stringent reaction conditions, typically the complete absence of

oxygen and water, as well as the sensitivity to most functional groups.15 The development

of controlled radical polymerization techniques combined the best of both attempts, com-

patibility with a wide range of functional monomers, low polydispersities, and control over

molecular weight and architecture. The key principle of controlled radical polymerizations

is based on reversible chain termination (Scheme 1).

3

Nitroxide Mediated Radical Polymerization

Polymer R Polymer R

Scheme 1: Basic principle of Controlled Radical Polymerizations: Reversible interchange between

dormant and active chain ends.

As a result, the polymer chains can grow simultaneously throughout the reaction with

very low concentrations of free radicals present at all times during the polymerization pro-

cess, thus minimizing irreversible termination reactions, such as recombination and dispro-

portionation. However, controlled radical polymerization techniques are no true living

systems1619 and termination reactions are not negligible. Nevertheless, they display impor-

tant characteristics of a living polymerization such as (i) a linear relation between molecu-

lar weight and conversion, (ii) molecular weight equal or close to the theoretical molecular

weight, (iii) low polydispersity, and (iv) defined end groups. For this reason, they are some-

times referred to as living free radical polymerization (LFRP) in the literature.

2.1.1 Nitroxide Mediated Radical Polymerization

Nitroxide mediated radical polymerization resulted from intentions of the australian Com-

monwealth Scientific and Industrial Research Organization (CSIRO) team around D. H.

Solomon to study the initiation of free radical polymerizations by trapping the propaga-

ting radical.20 The trapping agent used, 2,2,6,6-tetramethylpiperidinyloxy (TEMPO), does

not react with heteroatom-centered radicals but adds to carbon-centered radicals with near

diffusion-controlled rates.21 The fact that trapped radicals with more than one monomer

unit were found, in combination with the observed thermal instability of the formed

alkoxyamines, led to the assumption that thermal dissociation and reversible trapping can

lead to the controlled formation of oligomeric compounds.

Based on this initial work of Solomon, Rizzardo and Moad, low molecular weight polymers

and oligomers were obtained at temperatures of 80-100C.22 Low polydispersity polystyrene

was synthesized by further increasing the temperature to 130C in bulk using dibenzoyl per-

oxide (DBPO) as initiator and TEMPO as mediator.23 Since then ongoing research led to

4

Nitroxide Mediated Radical Polymerization

improved nitroxides12 which allow polymerization of many different monomer classes, e. g.,

acrylates, acrylamides, 1,3-dienes as well as acrylonitrile based monomers.

The polymerization mechanism of the nitroxide mediated radical polymerization is based on

a kinetic phenomenon called persistent radical effect24 (Scheme 2). After heterolytic cleavage

of the initiator into the initiating radical X and the mediating radical R, small amounts of

the initiating radical will undergo radical-radical coupling. The mediating radical R, how-

ever, cannot undergo homocoupling which results in an overall excess of mediating radicals

compared to initiating/propagating radicals.

X R X

X X

Coupling

+ R

M

X (M)n R

Polymerization

Scheme 2: Principle scheme for the nitroxide mediated radical polymerization.

The increasing efficiency of the formation of dormant chain ends with increasing excess

of mediating radicals regulates this equilibrium. The resulting small quantity of propagating

radicals with a large overall excess of dormant polymer chains gives rise to the persistent ra-

dical effect (PRE) and, hence, potential control over molecular weight and molecular weight

distribution. The upper limit for controlled molecular weight lays at 150000-200000 g mol1

for NMP polymerizations.25

5

Atom Transfer Radical Polymerization

2.1.2 Atom Transfer Radical Polymerization

The best established controlled radical polymerization technique to date is the transition

metal catalyzed atom transfer radical polymerization (ATRP) which was independently dis-

covered by Sawamoto et al. 26 and Matyjaszewski et al. 27 in 1995. The mechanism of ATRP

(Scheme 3) is based on a reversible redox process which generates the active species, usually

a CuI-complex. The oxidized species leads to a reversible abstraction of a halogen atom (Cl,

Br) from the dormant species R-X to generate the active radical R.

X R + Mtn Y/Ligandkact

kdeact

R

kp

Monomer

Termination

+ Mtn-1 Y/LigandX

Scheme 3: General mechanism of the atom transfer radical polymerization.

Molecular weights up to 150000 g mol1 have been successfully achieved by ATRP. How-

ever, at higher molecular weights increasing amounts of termination reactions suggest an

upper limit for controlled radical polymer synthesis.28 Such termination reactions mainly

include recombination and disproportionation and result from interactions of CuII species

with both the growing radical as well as its dormant species. In contrast to the normal

ATRP, where the initiating radicals are formed from an alkyl-halide and a transition metal

in its lower oxidation state, reverse ATRP uses classical initiators (e. g. AIBN) in combination

with a transition metal-complex in its higher oxidation state.2931 Various monomer types

have been polymerized by ATRP such as styrenes, (meth-)acrylates, (meth-)acrylamides and

others.13 However, some monomer classes are not accessible such as monomers contain-

ing acidic side chains, since they can protonate the ligands which form the corresponding

carboxylates, as well as halogenated alkenes, alkyl-substituted olefines, and vinyl esters. In

ATRP, likewise to other controlled polymerization techniques, the initiator should ensure a

fast initiation step compared to propagation.

6

Atom Transfer Radical Polymerization

Therefore, some general considerations for the initiator design should be taken into

account:

The initiator quality decreases from tertiary to secondary to primary alkyl halides and

addition of stabilizing groups, with relative efficiencies in the order CN > C(O)R >

C(O)OR > Ph > Cl > Me, will improve the initiator quality.3234

Although the bond strength for alkyl halides decreases in the order R-Cl > R-Br > R-I

and, hence, alkyl iodides should be the most efficient ATRP initiators, their use requires

certain precautions. For instance, their light sensitivity can lead to the formation of

metal iodide complexes (e. g., CuI2 which is thermodynamically unstable) or hetero-

lytic cleavage resulting in degenerative transfer reactions.35 Accordingly, bromides

and chlorides are preferentially used. Also pseudohalogens such as thiocyanates (SCN)

have been used36 but showed slow initiation for both styrene and methacrylate (MA).

The choice of catalyst may also influence the initiation efficiency. For example,

2-bromoisobutyrophenone initiates the controlled polymerization of methylmeth-

acrylate (MMA) when ruthenium or nickel complexes are used but turns out to be

useless in the copper-mediated ATRP. This is ascribed to the reduction of the resulting

electrophilic radical by the CuI species due to the lower redox potentials of copper-

based catalysts.

The order of reagent addition might be important. Upon slow addition of the catalyst

to the initiator/monomer solution the rate of termination during the initiation period

was found to be reduced.13

Beside the initiator and transition metal catalyst, the ligand is very important. Its major

role is to provide solubility for the transition-metal salt in the reaction medium and to adjust

the redox potential of the metal center. For the copper-mediated ATRP, nitrogen-containing

chelating ligands have predominantly been used not least because of the much lower effi-

ciency of sulfur, oxygen or phosphorus ligands due to unfavorable binding constants and/or

improper electronic effects. In principle, the activity of an ATRP ligand decreases with de-

creasing nitrogen atoms and increasing linking carbon atoms.37 The major disadvantage of

ATRP is, beside the relatively high temperatures usually used, the high amounts of (gener-

ally toxic) transition metal catalysts needed. These metal contaminants have to be removed

7

Reversible Addition-Fragmentation Chain Transfer Polymerization

from the products, especially in industrial use and, due to their toxicity, limit the use of ATRP

derived polymers. Recent developments led to improved methods to conduct ATRP poly-

merizations. In the so called activator generated by electron transfer (AGET) ATRP process

electron transfer is used instead of organic radicals to reduce the higher oxidation state tran-

sition metal.38 This allows the use of ATRP catalyst systems in their more stable higher ox-

idation states since these are reduced in situ before adding the initiator. In addition, the

amount of transition metals could be reduced to ppm quantities using activators regene-

rated by electron transfer (ARGET) ATRP.39 Reducing agents such as ascorbic acid or tin(II)

2-ethylhexanoate can continuously regenerate CuI from CuII during the polymerization and,

thus, ensure the catalytic amounts of transition metal needed.

2.1.3 Reversible Addition-Fragmentation Chain Transfer

Polymerization

Reversible addition-fragmentation chain transfer (RAFT) polymerization was discovered at

Australias CSIRO in the late 1990s.4042 In parallel, a similar polymerization technique,

macromolecular design by interchange of xanthate (MADIX) was invented in France.14 Both

RAFT and MADIX are based on an addition-fragmentation chain transfer mechanism.43,44

While MADIX refers to polymerizations mediated by xanthates, RAFT is usually mediated by

dithioesters or trithiocarbonates. Successful RAFT polymerization depends on the design of

the RAFT agent. To date many different RAFT agents have been reported.40,41,4556 Both R-

and Z-group allow for fine tuning of the performance of the RAFT agent. In principle the

R-group should be a good leaving group and liberate a relatively stable free radical with the

ability to initiate a polymerization. Therefore, the type and structure of the R-group can have

tremendous impact on the polymerization kinetics and the overall control. In contrast, the

Z-group is responsible for the ability of the C=S double bond to react with growing radicals

and the mean lifetime of the resulting intermediate radical formed.

The RAFT process is basically a free radical polymerization carried out in the presence

of a particular chain transfer agent, the so-called RAFT agent. Accordingly, traditional

methods to generate radicals from commercially available initiators such as 2,2-azobis(2-

methylpropionitrile) (AIBN) or 4,4-azobis(4-cyanovaleric acid) (V-501) are used. The initia-

tion step can also be carried out by photoinitiators or gamma irradiation.51,5759 Neglecting

8


the solvent cage effect, the produced radical I can either add to a monomer to initiate a

growing chain or add to the RAFT agent (Scheme 4). Due to the high transfer constants of

the most RAFT agents it is unlikely that more than a few monomers add to a growing chain

before the chain adds to a RAFT agent. Thus, via both pathways the intermediate radical is

reversibly formed which then can either fragment to give the RAFT agent and the growing

radical chain or cleave the R-group homolytically. The latter is the desired reaction pathway

and requires the R-group to be a better leaving group than the oligomer or polymer chain

and to be capable to initiate a polymerization. Hence, in the beginning of the polymeriza-

tion, the so-called pre-equilibrium, all initial RAFT agents should be activated and converted

into RAFT agents containing oligomeric or polymeric R-groups (macro-RAFT agents).

Pre-equilibrium:

Main equilibrium:

Pi R

PjPi

Z

SSR

Z

S SRPi

Z

S SPi+ +

+ +Z

SSPj

Z

S SPjPi

Z

S SPi

Scheme 4: Mechanism of the RAFT process.

The number of polymer chains is controlled by the amount of RAFT agents and not by the

number of initiator radicals produced. Once all RAFT agents are converted into macro-RAFT

agents, the main equilibrium starts. Here the reversible addition-fragmentation reactions

are dominant with a high amount of dormant chain ends compared to free radicals. In an

ideal RAFT polymerization all polymers are initiated by the R-group of the RAFT agent. As a

result the degree of polymerization is controlled by the ratio of monomer to RAFT agent and

the molar mass at a certain conversion can be calculated according to:

9


Mn,theor y =[Monomer ]0 MMonomer

[C T A]0 +2f[I ]0 (1ekd t )+MC T A (2.1)

where [Monomer]0 stands for the initial monomer concentration, MMonomer is the mole-

cular weight of the monomer, is the conversion, [CTA]0 is the concentration of RAFT agent,

f is the initiator efficiency, [I]0 is the initiator concentration, kd is the initiator decomposition

rate constant, and MC T A is the molecular weight of the RAFT agent. If the ratio of [CTA]0/[I]0

is high, initiation of polymer chains by initiator radicals can be neglected and equation 2.1

simplifies to:

Mn,theor y =[Monomer ]0 MMonomer

[C T A]0+MC T A (2.2)

The dithiobenzoate mediated RAFT polymerization involves two possible rate retarding

effects, (i) an induction period during the initial stage with almost no polymerization activity,

and (ii) rate retardation in the following phase with polymerization rates slower than in con-

ventional radical polymerization systems.60 These effects depend on the concentration of

RAFT agent. Rate retardation is only observed for polymerizations initiated by macro-RAFT

agents. While the CSIRO team explained the rate retardation effect by slow fragmentation

of the carbon-centered intermediate radical, Monteiro, Brouwer and Fukuda postulated a

cross-termination of the intermediate radical with a growing radical chain.60

In all theoretical models the retardation effect increases with increasing stability of the in-

termediate radical. In dithiobenzoate mediated RAFT systems delocalization of the radical

within the aromatic system is assumed to be responsible (Scheme 5).61

Replacing the phenyl group by a benzyl moiety led to significantly lower rate retardation

effects since the delocalization of the radical center is effectively suppressed.62 Further-

more, para-substituted dithiobenzoates showed significantly lower rate retardation effects.63

This observation indicates delocalized radicals and potential side reactions since the para-

position is less prone to radical attacks whereas the stability of the intermediate radical

should remain unchanged using the substituted RAFT agent. In order to investigate the

mechanistic aspects of the RAFT process, radical storage experiments were applied to cumyl

10


S SPjPi

S SPjPi

S SPjPi

S SPjPi

Scheme 5: Assumed resonance structures of the intermediate radical in dithiobenzoate mediated

RAFT polymerizations.

dithiobenzoate (CDB) mediated styrene and methylacrylate systems59,64 as well as to non-

retarding RAFT agents.65 Systems containing dithiobenzoate RAFT agents are capable to

store radicals for a certain time and, moreover, can induce a polymerization afterward with-

out the need of initiators. However, such experiments cannot be used to identify the chemi-

cal nature of these intermediates. In order to determine whether or not cross-termination

occurs, electronspray ionization mass spectrometry (ESI-MS) was used. Until now, no star

polymers could be detected by this technique.66,67 This lack of experimental evidence for

cross-termination reactions is a reason for continued debates about the origin of rate retar-

dation in the RAFT mechanism. 13C NMR measurements, in contrast, provided evidence

about the existence of 3- and 4-arm star polymers when high initial concentrations of RAFT

agents were used. This led to the assumption that the intermediate radicals undergo side

reactions with growing radical chains.68

On the theoretical level, the RAFT process can neither be fully explained using the cross-

termination model nor the slow-fragmentation model. The cross-termination model is in

good agreement with the experimentally observed kinetic aspects of the main equilibrium

but predicts significant concentrations of termination products which could not yet be de-

tected. On the other hand, the slow-fragmentation model is in agreement with the non-

stationary polymerization rate in the pre-equilibrium and the experimentally observed ra-

dical storage effects. However, the predicted intermediate radicals have not been observed

in ESR spectroscopy and it is contradictory to the observations for the main equilibrium.

A combined model which accounts for the differences in polymerization rate within the

pre- and the main equilibrium and which also includes yet unknown mechanistic aspects

of the RAFT process was developed by Buback who introduced the reversibility of the cross-

termination reaction into the theoretical calculations.69 This led to good results and ex-

plained the absence of star shaped polymers in the RAFT polymerizations. However, the

11


reaction mechanism still needs to be verified and these side reactions do not explain that

carbazoles show similar behavior to dithiobenzoates. Recently, Perrier et al. combined these

two conflicting models assuming reversible termination of the intermediate radicals only

for low molecular weight species but the slow fragmentation to be prominent during the

main equilibrium.70 Termination of short intermediate radicals would explain the absence

of 3-arm star polymers since the changes in molecular weight and hydrodynamic volume

are negligible for low molecular weight species. Furthermore, matrix-assisted laser desorp-

tion/ionization time-of-flight (MALDI-TOF) spectrometry experiments proved the existence

of such short cross-termination products.71 The basis for this assumption is that cross-

termination is diffusion controlled and, hence, small intermediates show much higher ter-

mination rate coefficients. In a following publication the same group predicted these short

intermediates to be maximum dimeric suggesting that cross-termination occurs only in the

very early stages of the RAFT process.72

In comparison to NMP and ATRP, RAFT polymerization is particularly robust and versatile

and can be applied to many different monomer classes. However, the choice of RAFT agent,

which commercial availability is limited, is crucial for successful polymer formation. More-

over, the sulfur containing end groups often result in red to yellow-colored polymers which

limits the application of RAFT in industrial processes without special treatment.

2.2 Block Copolymer Self-Assembly

Self-assembly of amphiphilic molecules into aggregates of different size and shape is

mainly determined by intermolecular interactions such as van der Waals, hydrophobic-

hydrophobic, hydrogen-bonding, or electrostatic interactions.73 Such systems are dynamic

in nature and external changes (e. g., pH, temperature, concentration, etc.) can lead to

changes of the formed aggregates. Both the thermodynamics of the self-organization pro-

cess and intra-aggregate forces between molecules within the same aggregate determine the

equilibrium structure formed. Considering the self-assembly of small amphiphilic lipids,

two major forces govern the self-organization process, (i) hydrophobic attraction of the hy-

drocarbon part and (ii) hydrophilic, ionic or electrostatic repulsion of the head groups. Thus,

at a certain head group area (Figure 1) the energy of repulsive interactions reaches a mini-

mum.

12


a0

v

lc

Figure 1: Schematic representation of an amphiphilic molecule with head group area a0, chain vol-

ume v, and chain length lc .73

The size of the formed aggregates is controlled by entropy which will favor the forma-

tion of particles with the smallest aggregation number. While larger structures will be en-

tropically unfavorable, smaller particles will suffer from increased repulsive interactions of

the head groups and, hence, be energetically disfavored. For low molecular weight lipids the

value of the packing parameter v/a0lc , where a0 is the optimal head group area, v is the hy-

drocarbon volume, and lc is the critical chain length, determines the shape of the resulting

aggregates (Figure 2).74

Spherical micelles are formed only when the optimal head group area a0 is large in com-

parison to the hydrocarbon volume v that the radius of the formed micelles does not exceed

the critical chain length lc . Geometrical considerations for a spherical micelle with radius rm

and aggregation number N give,

N = 4r2m

a0= 4r

3m

3v(2.3)

which becomes

r2m =3v

a0(2.4)

Hence, amphiphiles only assemble into spherical micelles if,

v

a0lc< 1

3(2.5)

With decreasing size of head group cylindrical micelles, bilayers, vesicles or inverted mi-

celles are formed (Figure 2). Changes in temperature can cause changes in both a0 as well as

lc depending on the amphiphile.

13


Spherical Micelles

Cylindrical Micelles

Flexibel Bilayers or Vesicles

Planar Bilayers

InvertedMicelles


micelles, cylindrical micelles, and vesicles depending on the relative block length within AB

diblock copolymers.

100 nm

100 nm

100 nm

Figure 3: Left: Schematically shown self-organization of diblock copolymers into spherical micelles,

cylindrical micelles, and vesicles; Right: (A-C) cryoTEM images of aggregates formed by PB-b-PEO;

(D-F), TEM images of aggregates formed by PS-b-PAA. A and D show vesicles; B and E show cylindrical

micelles; C and E show spherical micelles.81

Furthermore, two kinds of spherical micelles can be distinguished according to the rela-

tive lengths of the blocks in an AB diblock copolymer, (i) star-like micelles with a small hy-

drophobic core compared to the large corona, formed by the hydrophilic block, and (ii) crew-

cut micelles with a large hydrophobic core and stretched short hydrophilic coronal chains

(Figure 4). For simple amphiphilic block copolymers dissolution in a selective solvent for

one block is the most straight forward method for the preparation of micelles. However, de-

pending on the monomers used, non-equilibrium aggregates may be formed.82 In order to

obtain micelles closer to a thermodynamic equilibrium, the block copolymers are often dis-

solved first in a nonselective solvent followed by slow addition of a selective solvent for one

block. The commercially available amphiphilic block copolymers from poly(ethylene oxide)

and poly(propylene oxide) (PPO) are well-known to form micelles in aqueous solutions con-

taining a PPO core surrounded by a dense PEO layer and dangling PEO chains forming the

outer corona.83

15


star-like crew-cut

hydrophilic shell hydrophobic core

Figure 4: Schematic representation of a star-like (left) and a crew-cut (right) micelle.

In the case of diblock copolymers of polystyrene (PS) linked to PEO in aqueous solution,

two populations with a hydrodynamic diameter Dh of 40 nm and 150 nm have been observed

in TEM and light scattering studies.84 The authors concluded that the small aggregates are

regular micelles while the large particles consist of loose clustered micelles. Further investi-

gations using SANS, DLS and SLS proved the formation of anisotropic clusters of PS-b-PEO

micelles in aqueous solutions of up to 10 wt%.8588 These clusters may be the result of merg-

ing of initially formed micelles, as supported by controlled deaggregation of the clusters into

micelles upon the addition of toluene or inorganic salts. The reason for cluster formation

involves attractive interactions between the outer PEO chains such as hydrogen bonding or

hydrophobic interactions.89

The key problem of all block copolymer assemblies is how to control the structure and its

dimensions by choosing appropriately the length of each block and, moreover, how to trig-

ger structural changes such as transitions from spherical into cylindrical micelles by ex-

ternal stimuli. Extensive theoretical and computational work indicates that especially the

length of the hydrophilic corona forming block is crucial for the dimensions of the micelles

formed.90,91 Besides controlling the dimensions of spherical micelles, it would be highly

desirable to control the morphology of block copolymer aggregates with view on potential

applications in nanotechnology. Pioneering work of Eisenberg et al. demonstrated that for

PS-b-PAA block copolymers with a constant polystyrene block (DP = 200), a decreasing de-

gree of polymerization (DP) of the poly(acrylic acid) (PAA) block from DP = 21 to DP = 4

results in spherical, rod-like, vesicular, as well as crew-cut assemblies (Figure 5).5

16


Figure 5: PS-b-PAA block copolymers forming a) spherical (PS200-b-PAA21), b) rod-like (PS200-b-

PAA15), c) vesicular (PS200-b-PAA8), and d) crew-cut (PS200-b-PAA4) aggregates depending on the PAA

content.5

The morphology depends on three main factors, (i) the streching of the core forming

blocks, (ii) the core-corona interfacial energy, and (iii) repulsion between the corona form-

ing blocks. Changes in one of these three factors will result in thermodynamic instability and

lead to rearrangement into thermodynamically more stable morphologies.

Discher and Eisenberg proposed a general rule to predict the aggregate morphology

from the block copolymer composition where fhydr ophi l i c is the relative content of the

hydrophilic block:8

Spherical micelles are formed when fhydr ophi l i c > 45%.

Rod-like micelles are formed when fhydr ophi l i c < 50%.

Vesicles are formed when fhydr ophi l i c ~ 35%.

Inverted microstructures and crew-cut micelles are formed when fhydr ophi l i c < 25%.

17


However, this rule has no universal validity. The chemical nature of the blocks used as

well as the overall molecular weight of the block copolymers influence the aggregation in a

way that is not yet fully understood.

a) b)

c)

Figure 6: Cryo-TEM images of PEHA120-b-POEGA50-b-PFDA40 at 0.5 wt% in aqueous solutions a)

dispersed at 25C; b) dispersed at 25and annealed for 21d at 78C; c) dispersed at 70C.92

In addition, double hydrophobic ABC triblock copolymers containing two insoluble

blocks assembled into core-shell-corona micelles with the two hydrophobic blocks form-

ing the core and the shell and the hydrophilic block forming the solubilizing corona.9396

For polymers with the hydrophilic block in the middle, the aggregation behavior can be as-

sumed to be similar to ABA triblock copolymers as long the terminal blocks have a simi-

lar degree of polymerization. In the case of double hydrophilic terpolymers, the insoluble

block can be either in the middle or at one chain end. In the case of a terminal hydropho-

bic block, core-shell-corona micelles are expected. In contrast, when the hydrophobic block

is located in the middle of the block copolymer, non-centrosymmetric micelles can be ob-

served due to the heterogenous corona.97,98 Recently, so-called multicompartment micelles,

ABC triblock copolymers with a water-soluble shell and a segregated hydrophobic core have

been published.99,100 The hydrophobic core was composed of hydro- and fluorocarbon

containing blocks which showed segregation and the formation of two distinct domains.

For instance, cryo-TEM measurements of poly(ethylhexyl acrylate)-b-poly(oligoethylene

glycol monomethylether)-b-poly(tetrahydroperfluorodecyl acrylate) (PEHA120-b-POEGA50-

b-PFDA40) showed the segregated dark fluorocarbon domains within the self-assembled

18

Stimuli Responsive Block Copolymers

micelles (Figure 6).92 Simultaneous, selective uptake of lipophilic and fluorophilic guest

molecules into the corresponding hydrophobic polymer domains of multicompartment mi-

celles was monitored by UV-vis101 and NMR spectroscopy.102,103 Besides spherical micelles

and vesicular structures also helical104,105 or disk-like81 assemblies of block copolymers have

been observed (Figure 7).

Figure 7: A) Schematic illustration of self-assembled ABC block copolymers into disk-like micelles, B)

TEM images displaying disk-like micelles of PAA-b-PMA-b-PS triblock copolymers (amine/acid ratio

1/1) in a mixture of 40% water and 60% THF: (i) EDA as the counterion; (ii) EDDA as the counterion,

C) (i) tilted TEM images of disk-like micelles (EDDA as the counterion, amine/acid ratio 0.3/1), (ii)

CryoTEM images for the same sample where the disks are either parallel to the electron beam axis

(arrows 1) or perpendicular to the electron beam axis (arrows 2). Scale bars = 200 nm.81

2.2.1 Stimuli Responsive Block Copolymers

In aqueous solution stimuli sensitive polymers are typically switched from a hydrophilic to a

hydrophobic state or vice versa. Both physical (temperature, UV) and chemical (pH, redox)

stimuli can be applied in order to change the hydrophilicity of polymers. In some cases poly-

mers are even sensitive to more than one external stimuli. Poly(amine)s and poly(carboxylic

acid)s undergo distinct changes in hydrophilicity upon protonation or deprotonation, re-

spectively.106 Thermoresponsive behavior of polymers, in contrast, may be distinguished by

19


two different types. Either polymers are soluble above a certain temperature, exhibiting an

upper critical solution temperature (UCST), or they are soluble below a certain temperature,

showing a lower critical solution temperature (LCST). In contrast to the UCST phenomenon

which is caused by unfavorable enthalpy, the LCST is entropically driven.107 Rushbrooke

suggested already in 1938 that intermolecular hydrogen bonding may cause the LCST phe-

nomenon.108 In 1960 Freeman and Rowlinson reported that hydrocarbon polymers show a

LCST in hydrocarbon solvents.109 This finding was validated by a universal theory of Flory

on the LCST behavior of polymers in solution.110112 LCST behavior is widespread among

non-ionic hydrophilic polymers,113116 and is attributed to the balance of polymer-solvent

hydrogen bonding and polymer-polymer hydrophobic interactions.

O

O

O

O

O

O

O O

OO

O

OO

O

O

O

OO

O

O

O

O

O

O

O

OO

O

O

O

O

O

OO

O

H OH

HOH

HO H

HO

H

HOH

HO

H

HOH

HO H

H OH

H OH

HOH H

OH

HOH

HOH

O

OO O

O O

O O

OO O

O

O

O

O

O

O

O

O

O O

O OO

OOO

OO

O

O

O

O

O

O

HO

H

H OH

HO H

HO H

HO

H

HO

H

HO

H

HO

H

H OH

H OH

H OH

H OH

H OH

H OH

TLCST

Figure 8: Phase transition of thermoresponsive polymers in water.

Nevertheless, the exact position of such a phase transition can not be predicted by sim-

ple hydrophilic-hydrophobic balance considerations.115,117,118 Moreover, the exact phase

transition temperature of a polymer depends on additional factors such as molar mass, ar-

chitecture, end groups, concentration or added salts.113,116,119,120 While the UCST increases,

the LCST usually decreases with increasing molecular weight.121 In addition, an increase

in meso diads decreases the LCST while an increase in racemo diads increases the LCST

of poly(isoproylacrylamide) (PNIPAM).122,123 Isotactic PNIPAM was found to be more hy-

drophobic than atactic one with phase transition temperatures of about 24C.124 Thus, tac-

ticity of polymers seems to play an important role on their phase separation behavior. Also

the heating rate may effect the measured phase transition temperature markedly.125 An in-

crease of heating rate from 0.2 to 5 K/min can result in an increase in the apparent cloud

point values of up to 10C due to insufficient heat transfer.121,126

20


Figure 9: Thermodynamically stable random coil, crumpled coil, molten globule, and globule of

homo-PNIPAM chains in aqueous solution during the thermally induced collapse.127

The collapse of single PNIPAM chains in dilute solutions was intensively studied by

several analytical techniques. Though thermosensitive homopolymers usually precipitate

above their LCST, they show the formation of kinetically stable mesoglobules in highly dilute

solutions ( 106 g mol1).128,129 Wu and coworkers studied the coil-to-globule and globule-

to-coil transition using dynamic and static light scattering.128,130,131 After the coil-to-globule

transition, which was observed by a decrease of Rg /Rh from 1.50 to 0.56, the average chain

density decreased to 0.34 g/cm3 indicating that even the fully collapsed mesoglobules

still contain about 66% water. The authors suggested, that between the coil and the glo-

bule two other thermodynamically stable states exist, namely the crumpled coil and the

molten globule127,130 (Figure 9). Winnik et al. used light scattering in combination with

microcalorimetry for fluorescently labeled PNIPAM chains.129 Fluorescence spectroscopy

indicated that PNIPAM mesoglobules undergo a gradual transition from fluidlike particles

into hard spheres. Liu et al. reported on the observation of a two-stage transition of pyrene

labeled PNIPAM chains by a combination of fluorescence and stopped-flow techniques. A

first fast transition of randomly coiled PNIPAM into crumpled chains was followed by a slow

collapse into compact globules.132 Also Aseyev and coworkers observed the formation of

mesoglobules of PNIPAM, poly(N-vinyl caprolactam) (PVCL), and poly(vinyl methyl ether)

(PVME) homopolymers.133 Although theoretical calculations suggest that homopolymers

which form mesoglobular aggregates should assemble into cylindrical structures rather that

21


spherical,134 no such experimental observation has been made so far. A combination of

static and dynamic light scattering, instead, excluded cylindrical aggregates for PVCL, PNI-

PAM, and PVME homopolymers but suggested spherical particles with relatively narrow size

distributions.133

The simplest examples of stimuli-responsive block copolymers contain one permanently hy-

drophilic or hydrophobic block and one block which undergoes a phase transition from hy-

drophilic to hydrophobic when external stimuli such as temperature, pH, ionic strength or

UV-light are applied. Perrier et al. , for instance, synthesized diblock copolymers from PNI-

PAM and poly(dimethylacrylamide) (PDMA) varying the length of the PDMA block.135 The

authors stated that not only the relative length of the blocks determines whether micelles or

larger aggregates are formed but also the absolute length of the hydrophilic block. Moreover,

they demonstrated that the formed micelles are able to reversibly incorporate hydrophobic

dye molecules, in this case the relatively large 2,6-diphenyl-4-(2,4,6-triphenyl-N-pyridino)

phenolate also known as Reichardts dye (Figure 10). McCormick et al. synthesized block

copolymers from PNIPAM and PDMA by aqueous RAFT polymerization at room tempera-

ture and observed reversible micelle formation by passing the phase transition temperature

of PNIPAM.136 An increase of the relative length of the PNIPAM block led to larger particles

when the aqueous solutions were heated above 32-36C. Tenhu et al. studied diblock copoly-

mers from PNIPAM with hydrophobic blocks of polystyrene or poly(tert-butylmethacrylate)

obtained from RAFT polymerization.137 By variations of the length of the PNIPAM block sim-

ilar observations as by Perrier et al. were made. Not only the relative length of the blocks is

crucial for the formation of micellar aggregates. Longer PNIPAM chains led to larger aggre-

gates which was interpreted in a way that the long PNIPAM chains destabilize the forma-

tion of hydrophobic cores of polystyrene or poly(tert-butylmethacrylate). Interestingly, even

at prolonged elevated temperatures of 50C for several days the formed particles remained

stable and did not precipitate from solution. Marty, Destarac et al. synthesized PNIPAM-b-

poly(butylacrylate) (PBA) diblock copolymers with varying length of the PBA blocks.138 With

increasing PBA length the observed aggregates showed increasing hydrodynamic diameters.

This was explained by an increasing aggregation number Nag g of the formed micelles. More-

over, the PBA block led to a decrease of the phase transition temperature of the PNIPAM

block by about 6C. The cloud point was decreased even further when the length of the PBA

block increased. Complementary results were obtained by Armes et al. for AB block copoly-

22


mers from methyl vinyl ether (MVE) and methyl triethylene glycol vinyl ether (MTEGVE).139

The cloud points of the block copolymers increased from 18C to 84C with increasing length

of the more hydrophilic polyMTEGVE block.

Figure 10: Bathochromic and hypsochromic shift of Reichardts betaine dye in an aqueous solution of

PDMA58-b-PNIPAM61 at a concentration of 1 w% upon heating and cooling between r.t. and 55C.135

Especially block copolymers from PNIPAM and PEO found much attention through-

out the recent years, because of the lower critical solution temperature of PNIPAM (32C)

close to human body temperature (37C) and the biocompatibility of PEO.113,140143 Such

block copolymers are expected to be interesting candidates for drug delivery and biomed-

ical applications.115,140,144149 For instance, Feijen et al. synthesized PEO-b-PNIPAM block

copolymers which self-assembled into spherical micelles in aqueous solution once the tem-

perature was increased above the cloud point of the PNIPAM block at about 31C.141 Hennink

et al. studied the self-aggregation of PEO-b-PNIPAM block copolymers in dilute aqueous so-

lution, too.150 With increasing PNIPAM chain length the particle size was found to decrease.

These findings were interpreted in terms of increased dehydration of the thermosensitive

block which results in more densely packed hydrophobic cores. These observations are in

direct contrast to the results obtained by Marty and Desterac,138 who found larger particles

with increasing length of the hydrophobic block (vide supra). Moreover, the heating rate ap-

peared to influence the size of the formed aggregates with a fast heating protocol resulting

in smaller particles than observed for slow heating rates. In addition, the particles formed

by fast heating had lower polydispersity indices than the ones from slow heating. Based on

these finding the authors tested a heat shock protocol. Relatively small amounts of polymer

solution below the cloud point temperature were added to water at 40C, thus well above

23


the LCST of PNIPAM. Such rapid heating led to even smaller particles with a Dh of 50 nm

and very low polydispersities around 0.04. Pispas et al. observed the same trend for dif-

ferent heating protocols of PEO-b-PNIPAM diblock copolymers.125 Moreover, Shi et al. ob-

served a concentration dependence of micellar size and size distribution of PEO-b-PNIPAM

diblock copolymers. Surprisingly, higher concentrations led to smaller and more narrowly

distributed aggregates than smaller concentrations at which loose micellar assemblies or

even clusters appeared.142

More dynamic aggregation behavior was observed for double responsive diblock copoly-

mers. By the use of orthogonal stimuli or by the combination of one LCST and one

UCST block, so called schizophrenic block copolymers can be obtained in which micelles

and reverse micelles can be selectively formed according to the external stimulus applied.

For instance, double thermoresponsive block copolymers from PNIPAM and poly(3-[N-(3-

methacrylamidopropyl)-N,N-dimethyl]ammoniopropane sulfonate) (PSPP) having a LCST

and a UCST block, respectively, have been synthesized.151 At low temperatures PSPP-core

PNIPAM-shell micelles are obtained, at intermediate temperatures the block copolymers

are molecularly dissolved whereas at high temperatures reverse micelles with a PNIPAM

core and a PSPP shell are formed. Similar systems have also been reported by Maeda and

Armes.152,153 In addition, schizophrenic diblock copolymers sensitive to changes in pH val-

ues have been reported. A zwitterionic block copolymer of poly(4-vinylbenzoic acid) (PVBA)

and poly(2-N-(morpholino)ethyl methacrylate) (PMEMA) showed PVBA-core micelles be-

low pH 6. Increasing the pH above 6 led to dissolved polymers which aggregated into

PMEMA-core micelles at elevated temperature or in the presence of Na2SO4.154 In addition,

even triple responsive diblock copolymers exhibiting a third redox155 or sugar response156,157

were published recently but especially the redox switch is often not reversible. Such

schizophrenic block copolymers are especially interesting due to their ability to aggregate

into different structures under changing conditions. Double responsive diblock copolymers

with a thermo- and a pH-responsive block from PNIPAM and poly(N,N-diethylaminoethyl

methacrylate) (PDEAEMA), respectively, could even be switched from micellar into vesicular

aggregates in response to changes of the external conditions158 (Figure 11).

24


a)

b)

pH

pH

Temp

Temp

Micelles inverse Micelles

Micelles Vesicles

Figure 11: Schizophrenic aggregation behavior of (a) PDEAEMA98-b-PNIPAM209 and (b)

PDEAEMA98-b-PNIPAM392. Adapted from ref.158

Beside diblock copolymers, multi responsive terpolymers with ABA or BAB sequence,

containing a responsive block and a permanently hydrophilic B block, are well-known for

their rich aggregation behavior. While BAB triblock copolymers often form spherical mi-

celles with a core forming A block and corona forming B blocks, the situation becomes more

complex for ABA systems. Theoretical discussion of the formation of flower-like micelles

in which the dissolved middle block has to loop in order to incorporate both hydropho-

bic A blocks into the core were done by Tirrell and coworkers.159 Calculations suggested

that only polymers with very short hydrophobic A blocks will form flower-like micelles while

for longer A blocks mixed star-/flower-micelles, with partially free dangling chain ends, are

more probable. The assumption of flower-micelles formed by ABA triblocks was experimen-

tally supported by the findings that the investigated aggregates had dimensions of those

formed by diblock copolymers of half the molecular weight.159,160 Moreover, when the re-

lative block length of the middle block was decreased below the size of the hydrophobic A

blocks, no aggregation was observed. Likewise to their diblock counterparts, changes in size

and morphology of triblock copolymer aggregates can be induced by changes of the solvent

qualities or upon introducing stimuli-sensitive blocks. Wang et al. synthesized poly(stearyl

methacrylate)-b-PNIPAM-b-poly(stearyl methacrylate) (PSMA-b-PNIPAM-b-PSMA) triblock

copolymers which showed morphological transitions from vesicular into micellar structures

with increasing water content in THF/water mixtures.161

25


ABC triblocks with stimuli-sensitive blocks have been described by Eisenberg and cowork-

ers who reported on the self-assembly of PAA26-b-PS890-b-P4VP40 as function of pH in

DMF/THF/H2O mixtures.162 At low pH, vesicles with the P4VP blocks forming the outer shell

and PAA blocks forming the inner shell were formed. At intermediate pH values, spherical

and ellipsoidal aggregates were found while at high pH again vesicles, this time with outer

PAA and inner P4VP block, were observed. Thus, an interconversion of vesicles with either

outer PAA or P4VP blocks was possible by changing the pH of the solution (Figure 12).

Figure 12: Schematic representation of the pH induced inversion of vesicles formed from PAA26-b-

PS890-b-P4VP40 triblock copolymers.162

P2VP58-b-PAA924-b-PBMA48 terpolymers also showed morphological changes at differ-

ent pH values and temperatures in aqueous solutions.163 At pH 1, changes in tempera-

ture led to either mesoglobules (T < 20C) or swollen micelles (T > 20C). An increase in

pH from 8 to 11 and then to 12 led to spheres, toroidal nanostructures and finally to mi-

crogels, respectively. Another example for double responsive ABC triblock coplymers is

the aggregation of PEO-b-P4VP-b-PNIPAM in aqueous solution.164 At 25C a unimer-to-

micelle transition occured when the pH was increased from 2 to 6.5. At elevated tem-

peratures, above the cloud point of the PNIPAM block, micellar clusters could be con-

verted into core-shell-corona micelles upon increasing the pH. Interestingly, even mor-

phological changes from spherical into worm-like micelles were reported for double hy-

drophilic ABC triblock copolymers from PEO114-b-PBA250-b-PDEAM135 (poly(diethyl acryl-

amide) (PDEAM)), upon changes of the solution temperature165 (Figure 13). In addition,

schizophrenic aggregation behavior of ABC triblock copolymers could be obtained from

poly(2-(diethylamino)ethyl methacrylate)-b-poly(2-(dimethylamino)ethyl methacrylate)-b-

poly(2-(N-morpholino)ethyl methacrylate) (PDEA-b-PDMA-b-PMEMA) by changes in pH

and addition of Na2SO4.166

26


Figure 13: Worm-like and spherical micelles formed from double hydrophilic ABC triblock copoly-

mers depending on the solution temperature.165

At pH 7.6 PDEA-core, PDMA-shell, PMEMA-corona micelles were formed which inversed

to PMEMA-core, PDMA-shell, PDEA-corona micelles when Na2SO4 was added. Finally, ABC

terpolymers can also form helical105 or hamburger-like167 superstructures under proper sol-

vent conditions.

Consequently, triple responsive ABC triblock copolymers are assumed to provide even more

opportunities to control the self-aggregation and, moreover, trigger morphological changes

stepwise. However, until now only very few examples of triple responsive terpolymers have

been reported, all of which comprising three temperature responsive blocks. Aoshima

et al. reported on the synthesis and aggregation behavior of triple thermoresponsive block

copolymers from 2-ethoxyethyl vinyl ether (cloud point 20C), 2-methoxyethyl vinyl ether

(cloud point 41C) and 2-(2-ethoxy)ethoxyethyl vinyl ether (cloud point 64C) obtained

from sequential living cationic polymerization.168 Such ABC polymers showed a multi-

step aggregation process from unimers to micelles followed by physical gelation and finally

precipitation upon increasing the temperature. More recently, Zhu et al. reported on the

multi-step phase transitions of triple thermoresponsive terpolymers in dilute aqueous so-

lutions and studied their self-assembly by a combination of dynamic and static light scat-

tering, NMR spectroscopy as well as ultrasensitive differential scanning calorimetry.169,170

ABC triblock copolymers with thermoresponsive blocks from poly(N-propylacrylamide)

(PNPAM, cloud point 22C), poly(N-isopropylacrylamide) (cloud point 32C) and poly(N,N-

27


ethylmethylacrylamide) (PNEMAM, cloud point 56C) showed a multi-step self-organization

from unimers into micelles or micellar clusters depending on the chain length of the

poly(N,N-ethylmethylacrylamide) block, i. e., only a long poly(N,N-ethylmethylacrylamide)

block was able to stabilize micellar aggregates. Whereas the influence of the chain length

of the terminal high-LCST block on the aggregation process has been studied, the effect

of changing the block sequence has not been explained. However, although the triblock

copolymers PNPAM124-b-PNIPAM60-b-PNEMAM44 showed three changes in transmission

intensity with increasing temperature, dynamic light scattering displayed only one thermal

transition for homo-, di-, and triblock copolymers (Figure 14).

Figure 14: Turbidity (left) and dynamic light scattering (right) measurements of PNPAM124-b-

PNIPAM60-b-PNEMAM44 .169

After passing the cloud point of the PNPAM block at about 24C, aggregates with a Dh

of ~ 150 nm were observed for PNPAM124-b-PNIPAM60-b-PNEMAM44. Further heating led

to a gradual decrease of Dh without any indication of a second pronounced change. Varia-

tions in the relative block length, PNPAM124-b-PNIPAM80-b-PNEMAM44 and PNPAM124-b-

PNIPAM80-b-PNEMAM160, then led to better results and changes of the hydrodynamic dia-

meter with temperature became visible upon heating their aqueous solutions from 15-70C

(Figure 15).170

28


Figure 15: Hydrodynamic diameter (top) and apparent molar mass (bottom) of PNPAM124-b-

PNIPAM80-b-PNEMAM44 () and PNPAM124-b-PNIPAM80-b-PNEMAM160 () as function of tempe-rature.170

While the dynamic light scattering curves show more than a single transition during the

heating process the interpretation and proposed aggregation pathway (Figure 16) is ques-

tionable at least for the polymer with the shorter PNEMAM block . The smallest observed

aggregates have a Dh of about 160 nm while its contour length is 62 nm. Thus, even in the

fully extended state no single micellar aggregates with a hydrodynamic diameter of mini-

mum 160 nm can be formed.

29


Figure 16: Proposed aggregation pathway of PNPAM124-b-PNIPAM80-b-PNEMAM44.169

2.3 Alternating Copolymerization

Nylon 6,6 is maybe one of the most famous alternating copolymers due to the wide range

of commercial applications. Nylon 6,6 can be obtained by polycondensation of the cor-

responding diamines and dicarboxylic acids. In principle, the polycondensation or step-

growth polymerization of A-A and B-B monomers will always result in alternating copoly-

mers since each monomer cannot react with itself. Thus, crosspropagation is the only pos-

sible polymerization pathway. In chain growth systems such as a common radical copoly-

merization of two monomers A and B, however, four different chain propagation reactions

can take place, namely A as well as B can add either to an active chain of A or B. These four

propagation pathways are governed by the propagation rate constants kab2 , kaa2 , k

bb2 and k

ba2 .

The resulting composition of the formed copolymers is then determined by the ratios of the

corresponding propagation rate constants

= kab2

kaa2; = k

bb2

kba2(2.6)

Accordingly, if a copolymerization of A and B is started in a molar ratio of B/A, the molar

ratio within the resulting polymer b/a can be calculated according to:171

30

Alternating Copolymers of Maleic Anhydride and Styrene

b

a= B

A B + A

B + A (2.7)

Alternating copolymers are usually only obtained by radical polymerization, if the

monomer pair is forming charge-transfer complexes (CTC) which then homopolymerize, or

if the crosspropagation rate constants are much higher than the homopolymerization rates.

N-Vinylcarbazole, for instance, was reported to form 1:1 alternating copolymers with fuma-

ronitrile and diethyl fumarate.172,173 Also alternating copolymers of styrene and acrylonitrile

were synthesized by free radical polymerization in the presence of zinc chloride.174 In the

special case of styrene (A) and maleic anhydride (B), the latter does not undergo homopoly-

merization and, in addition, the propagation rate for styrene terminated polymers is much

higher toward maleic anhydride than styrene monomers. As a result, kbb2 becomes zero, thus,

also becomes zero and equation 2.7 simplifies to:

b

a= 1+ 1

A

B(2.8)

2.3.1 Alternating Copolymers of Maleic Anhydride and

Styrene

Since the 1940s the copolymerization of styrene and maleic anhydride (MAn) is known

to proceed in an alternating fashion.171,175 However, there is still disagreement about the

origin of the alternating nature of this monomer pair. Mainly two, incompatible, expla-

nations are discussed in the literature.176 On the one hand the alternation is claimed to

arise from charge-transfer-complexes which show higher reactivity against the growing ra-

dical than uncomplexed monomers.177,178 On the other hand the alternating copolymer-

ization of styrene and maleic anhydride is discussed in terms of different reactivities of the

monomers resulting in marked preferences for crosspropagation reactions.179 Sometimes

it is argued that this general tendency is enhanced by donor-acceptor interactions between

the growing radical chain ends and adjacent monomers. In the case of maleic anhydride

and N-substituted maleimides with styrene, the very low tendency of maleic anhydride and

31

Alternating Copolymers of Maleic Anhydride and Styrene

N-substituted maleimides toward homopolymerization and the extremely favored crosspro-

pagation with styrene can be accounted for the alternating nature of the polymerization pro-

cess.180,181

However, the former is still an issue of discussion since UV and NMR measurements proved

the existence of styrene-maleic anhydride donor-acceptor complexes under usual polymer-

ization conditions.177 In solvents such as methyl ethyl ketone or DMSO competitive com-

plexation of the monomers by the solvent molecules takes place. However, the alternat-

ing feature of the copolymerization alone cannot prove the involvement of CTCs. For in-

stance, the relative reactivity of styrene and MAn with donor-type radicals, e. g., cyclohexyl

radicals, was tested and showed that MAn was 850 times more reactive than styrene.182

Likewise, acceptor type radicals, benzoyloxy radicals, reacted 50 times faster with styrene

than with MAn.183,184 Thus, the alternation can also arise from the different reactivities

of the monomers favoring crosspropagation. Moreover, the question has to be addressed

whether the CTCs have a higher reactivity toward a growing polymer chain than uncom-

plexed monomers since this cannot be assumed a priori. In fact, theoretical calculations are

difficult for this problem since the structure of the formed styrene-MAn complex can only

be assumed from 1H NMR data but has large impact on the potential reactivity. Theoret-

ical calculations, however, have shown that CTCs may indeed participate in the polymer-

ization but only one reaction proceeds faster for the complex, namely the addition to an

active styrene end. Electron spin resonance (ESR) spectroscopy as well as trapping of ac-

tive radical chain ends was suggested to give further information about the polymerization

mechanism. Indeed, by trapping styrene-MAn mixtures with 2-methyl-2-nitrosopropane at

50C only styrene terminated molecules could be found in agreement with a polymerization

of CTCs which add with their MAn side to the active styrene end.185 However, the trapping

agent used is not very efficient in trapping maleic anhydride radicals and, therefore, the ob-

servation made is not a proof for the proposed mechanism.176

The latter, in contrast, is accounted for by the penultimate unit model (PUM).186 Here not

only the terminal unit determines the crosspropagation rate constant but also the penul-

timate unit (ki i i = k j i i ). Especially the decreasing content of alternation with increasingtemperature was often used to support the complex participation model (CPM). However,

copolymerizations in the absence of CTCs are known to proceed more randomly at higher

temperatures and the temperature dependence of copolymer composition vs. monomer

32

Copolymerization of N-substituted Maleimides with Styrene

feed can be described by both models (CPM and PUM). Thus, in order to rule out one of

these two models other experimental data are required. Determinations of average propaga-

tion rate coefficients as function of comonomer feed compositions using pulsed laser poly-

merization were used by Klumperman et al. for the MAn-styrene system.187 The observed

increase of the rate coefficients with increasing MAn fraction could be explained using the

PUM but not by the CPM. Reductive demercuration was used to generate benzyl radicals in

N-phenylmaleimide (NPhM) styrene mixtures in order to investigate the concerted addition

of a styrene terminated polymer to a CTC of a N-substituted maleimide and styrene.188 The

results showed almost exclusively single addition of styrene ruling out a concerted addition

of a 1:1 maleimide-styrene complex. Further indication for the absence of CTC in RAFT-

mediated styrene-MAn copolymerizations were reported using in situ 1H NMR spectroscopy

during the initiation period.189 The results showed that, depending on the structure of the

RAFT agent used, selective addition to a single monomer unit of either MAn or styrene takes

place. Within the early stages of the copolymerization only one monomer unit adds to the

growing polymer chain before termination takes place. In the case of complex participation,

however, the styrene-MAn couple should be added to the chain end.

2.3.2 Copolymerization of N-substituted Maleimides with

Styrene

Compared to maleic anhydride, the copolymerization of N-substituted maleimides with

styrene is not strongly alternating190192 since the styrene content can be varied depending

on the monomer feed.176 This aspect is also important for the discussion of CTCs involved in

the polymerization mechanism since styrene rich copolymers can arise only from incorpora-

tion of non-complexed monomers. Moreover, in contrast to MAn, N-substituted maleimides

can be homopolymerized by anionic as well as radical polymerization.193196

Many different N-substituted maleimides have been used as comonomers in order to in-

crease the solubility and thermal stability,196,197 or functionalize polymer chains.180,181 Re-

cent examples by Lutz et al. showed that the monomer sequence can be conveniently con-

trolled even in radical polymerization when the kinetics are well known.180,181,198200 The

sequential addition of various different maleimides to a growing styrene chain led to prepro-

grammed distributions of functional side chain groups and up to four different maleimides

could be incorporated along one polystyrene chain (Figure 17).

33

One-Step Synthesis of Diblock Copolymers

This concept works because the maleimides are incorporated immediately after addition

and result in very narrow domains of alternating copolymer parts.

N OO

R1

N OO

R2

N OO

R3

N OO

R4

t0 t1 t2 t3

convS ~ 0.25 convS ~ 0.50 convS ~ 0.75

Living chain-growth

Controlled monomer addition

Figure 17: General concept for the sequential addition of various functional maleimides to the poly-

merization of styrene by ATRP according to Lutz et al. 201

2.3.3 One-Step Synthesis of Diblock Copolymers

In comparison to commonly applied sequential synthesis of block copolymers by con-

trolled radical polymerization techniques, the one-step formation of block copolymers

would be a significant advantage. The aforementioned alternating copolymerization of

styrene and MAn or N-substituted maleimides is a promising candidate within this con-

text. Recently a few reports were published on the one-step formation of AB diblock

copolymers. The NMP polymerization of a 9:1 mixture of styrene and MAn as reported

by Hawker et al. produced a poly(styrene-co-MAn)-b-polystyrene (P(S-co-MAn)-b-PS) block

copolymer.202 During the initial phase of the polymerization the much faster crosspro-

pagation takes place until MAn is consumed, followed by the homopolymerization of

styrene. However, NMP did not result in an alternating block but in a copolymer with

a 2:1 content styrene:MAn. By the use of RAFT, Li et al. obtained P(S-alt-MAn)-b-PS in

a one-step synthesis.203 Hydrolysis of the MAn units gave an amphiphilic block copoly-

Synthesis and self-assembly of multiple thermoresponsive ...

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